Dasatinib combined with docetaxel for castration-resistant prostate cancer: Results from a phase 1-2 study

John C. Araujo, Paul Mathew, Andrew J. Armstrong, Edward L. Braud, Edwin Posadas, Mathew Lonberg, Gary E. Gallick, Géralyn C. Trudel, Prashni Paliwal, Shruti Agrawal, Christopher J. Logothetis

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Abstract

BACKGROUND: To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor. METHODS: In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m 2 every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m 2 every 21 days. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied. RESULTS: Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months. CONCLUSIONS: The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalCancer
Volume118
Issue number1
DOIs
StatePublished - Jan 1 2012

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Keywords

  • bone
  • dasatinib
  • docetaxel
  • metastases
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Araujo, J. C., Mathew, P., Armstrong, A. J., Braud, E. L., Posadas, E., Lonberg, M., Gallick, G. E., Trudel, G. C., Paliwal, P., Agrawal, S., & Logothetis, C. J. (2012). Dasatinib combined with docetaxel for castration-resistant prostate cancer: Results from a phase 1-2 study. Cancer, 118(1), 63-71. https://doi.org/10.1002/cncr.26204